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However, the role of PGRMC2 in ischemic stroke remains unexplored. The present study sought to determine the regulatory role of PGRMC2 in ischemic stroke.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male C57BL\/6J mice were subjected to middle cerebral artery occlusion (MCAO). The protein expression level and localization of PGRMC2 were examined by western blotting and immunofluorescence staining. The gain\u2010of\u2010function ligand of PGRMC2 (CPAG\u20101, 45\u2009mg\/kg) was intraperitoneally injected into sham\/MCAO mice, and brain infarction, blood\u2013brain barrier (BBB) leakage, and sensorimotor functions were evaluated by magnetic resonance imaging, brain water content, Evans blue extravasation, immunofluorescence staining, and neurobehavioral tests. The astrocyte and microglial activation, neuronal functions, and gene expression profiles were revealed by RNA sequencing, qPCR, western blotting, and immunofluorescence staining after surgery and CPAG\u20101 treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Progesterone receptor membrane component 2 was elevated in different brain cells after ischemic stroke. Intraperitoneal delivery of CPAG\u20101 reduced infarct size, brain edema, BBB leakage, astrocyte and microglial activation, and neuronal death, and improved sensorimotor deficits after ischemic stroke.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CPAG\u20101 acts as a novel neuroprotective compound that could reduce neuropathologic damage and improve functional recovery after ischemic stroke.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14122","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T09:26:23Z","timestamp":1676539583000},"page":"1585-1601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Gain\u2010of\u2010function of progesterone receptor membrane component 2 ameliorates ischemic brain 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